A 1,4-dihydropyridine compound which contains two different carboxylic acid esters each other at the 3- and 5-positions of the dihydropyridine ring possesses an asymmetric carbon atom at the 4-position thereof and thus has two optical isomers. It is reported that recent studies on biological properties of these optically active compounds reveal differences of the isomers in pharmacological activity, kinetics in vivo and safety (K. Tamazawa et al., J. Med. Chem., 29, 2504 (1986)). Where these compounds with an asymmetric carbon atom are employed as pharmaceuticals, it has been a general tendency to administer only one of the isomers that is preferable as a pharmaceutical, under such a consensus that any undesirable load should not be borne to the living body. From such a viewpoint, studies have been focused on a process for preparing optically active 1,4-dihydropyridine derivatives. As a conventional process for synthesis of optically active 1,4-dihydropyridine derivatives, there is known a process for introducing a desired ester residue into a (4R)-1,4-dihydropyridinecarboxylic acid mono-ester as an intermediate (A. Ashimori et al., Chem. Pharm. Bull., 39, 108 (1991)). For preparing this optically active intermediate, (4R)-1,4-dihydropyridine-3,5-dicarboxylic acid mono-ester, there are known the chemical process by Shibanuma et al. (Chem. Pharm. Bull., 28, 2809 (1980)) and the enzymatic methods by Achiwa et al. (Tetrahedron Letters, 32, 5805 (1991)) and by Charles J. Sih et al. (Tetrahedron Letters, 32, 3465 (1991)). However, any method for asymmetric direct hydrolysis of diesters by microbiological technique is not disclosed in these publications.
The chemical synthesis of optically active (4R)-1,4-dihydropyridine-3,5-dicarboxylic acid mono-ester described above encounters disadvantages that not only the process requires a protective group for the amino group on the dihydropyridine ring but the formed mono-carboxylic acid racemate requires optical resolution since the reaction is not asymmetric hydrolysis.
On the other hand, the process by Achiwa et al. comprises using as a substrate a dihydropyridine ester derivative having pivaloyloxymethyl at the 3- and 5-positions of the dihydropyridine ring, enzymatically hydrolyzing one of the esters asymmetrically to form an optically active dihydropyridine monocarboxylic acid derivative as an intermediate for synthesis of pharmaceuticals. However, this process involves a defect that the overall yield is not very good, because the process requires a number of steps such as synthesis of the substrate, conversion of pivaloyloxymethyl into other substituents to form compounds useful as pharmaceuticals.
According to the process of Sih et al. acetoxymethyl ester is used instead of pivaloyloxymethyl ester in the process of Achiwa et al. Both processes are basically the same.
It has thus been desired to develop a process for efficiently preparing optically active (4R)-1,4-dihydropyridine 3,5-dicarboxylic acid mono-esters.